Dendritic cells (DCs) within the mucosal surfaces are in a prime location to encounter immunodeficiency viruses (HIV/SIV) that cross epithelial barriers during mucosal transmission. Here lies the paradox, since DCs capturing HIV/SIV should migrate to the draining lymph nodes and initiative virus-specific immunity while the same environment drives rapid virus growth and efficient spread of virus between cells. Moreover, damaging the mucosae (by infection or physical trauma) likely activates DCs enhancing the susceptibility to infection. Hence, it is essential to identify how virus interacts with DCs under various conditions of activation and how they then spread virus between cells. Dcs express molecules such as CD4, chemokine receptors, and the C-type lectin DC-SIGN, all of which have been implicated in virus capture and infection in DC-T cell cultures. Due to the low frequency of virus- carrying DCs (whether they are in infected or not) it is difficult to resolve the exact contribution of these (and other) molecules in binding and entry. It is possible that virus is (i) trapped on the DC surface, (ii) internalized by the endocytically active DCs , and/or (iii) fuses with the DC membrane to infect the cells. We will use a chemically inactivated, yet conserved form of virus, which interacts normally with receptors on the cell surface and allows us to a higher doses of non-infectious virus. Our preliminary studies revealed the striking feature that both immature and mature DCs capture and internalized large numbers of virions. Therefore, this approach will enable us to visualize the virus and address several specific questions. 1. What are cellular requirements for virus binding and entry into immature vs. mature DCs? 2. Where is the virus located within DCs and how long does it remain there? 3. Is virus transmitted between distinct DC subsets? 4. Is immune-complexed virus targeted to DCs enhancing uptake, internalization, and transmission? These investigations will reveal critical details about how an immunodeficiency virus can bind to DCs, how the virus gains entry into the DC, and where whole virus can reside within the cell. We will ascertain (i) how different DC populations manipulate the virus, (ii) what stimulating the DC does to DC-associated virons, and (iii) whether virus that is bound by virus-specific antibodies is directed to DCs. Knowing how DCs deal with HIV/SIV is crucial to unravel the cellular and molecular mechanisms, to design strategies to prevent the onset and spread of infection.